RX Pad: Reducing Relapses Through Opioid Maintenance Therapy

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Opioid Maintenance Therapy can lower the endless quest for the next high.

Opioid misuse and abuse is rampant in the United States, with an estimated three million people suffering from an opioid use disorder.(1) A key contributor to the ongoing epidemic is the fact that treatment of opioid addiction is notoriously difficult. Use of behavioral interventions alone results in a depressingly high relapse rate of 80%.(2)

Medication-assisted detoxification programs have similarly poor long-term success rates. Experts increasingly view addiction in a chronic disease model with a relapsing and remitting course, similar to diabetes or hypertension.(1) Although patients may experience periods of sobriety, abstinence from opioids is often incomplete and patients are vulnerable to relapse.

To date, the most effective treatment for retaining individuals with opioid addiction in treatment programs and suppressing use of heroin and other illicit opioids is opioid maintenance therapy (OMT).(3,4) OMT patients take a daily prescribed opioid agonist, such as methadone, or a partial agonist like buprenorphine long-term after the acute withdrawal period.

Patients with opioid use disorders, many of whom are on OMT, commonly seek care in emergency department for treatment of their substance abuse disorder, comorbid medical or psychiatric conditions, or other illnesses and injuries. Therefore it is important for emergency physicians to understand the basics of OMT as well as how it affects our management of ED patients with acutely painful conditions. There is new data suggesting buprenorphine may be useful in the management of acute opioid withdrawal. Some emergency physicians already prescribe buprenorphine for acute withdrawal. Could it become the standard practice?

Opioid Maintenance Therapy

OMT is used to treat opioid addiction beyond the initial withdrawal period. The idea is that patients take just enough of an opioid agonist to prevent withdrawal symptoms, but not enough to cause a drug-related ‘high.’ This frees patients to engage in healthy activities such as work, school and family life, rather than planning the next drug fix. While some patients eventually transition off OMT, many stay on OMT for years or even decades, finding that it allows them to maintain some normalcy in their lives and limit relapse episodes. The two primary options for OMT are methadone and buprenorphine, and the two have similar efficacy in maintenance of sobriety.(4)

Methadone

Methadone is a synthetic opioid agonist with activity at the mu opioid receptor. It has been in use since the 1960s, and has a long track record of safety and efficacy. When dosed appropriately, methadone prevents withdrawal symptoms, but does not result in euphoria. It has a long half-life, which allows for once-a-day dosing. Methadone is formulated as an oral liquid or a pill.

Long-term treatment with methadone results in one-year retention rates in treatment of approximately 60%, much higher than behavioral interventions alone.(2)  However, the downside of methadone is that it must be administered through specialized clinics, a setup intended to minimize drug diversion, misuse and overdose. Patients must go to the clinic daily and take their allotted dose under the watchful eye of a nurse. Conflict with work schedules and transportation problems make methadone clinics prohibitive for many patients. Clinics may also not be available in rural areas, where the opioid epidemic is particularly rampant, but the population is more spread out.Methadone can increase the QT interval, but rarely beyond the 500 msec threshold that is associated with arrhythmias.

Most cases of torsades de pointes have been seen in patients on large, multiple daily doses of methadone for pain, though it has been rarely reported in patients on once daily opioid maintenance therapy.(2,5)  In patients at risk for QT prolongation, such as those with underlying cardiac conduction abnormalities, hypokalemia, hypomagnesemia or concomitant use of medications that are known to increase the QT interval, methadone should only be used if the benefit of OMT outweighs the risk of QT prolongation and arrhythmias. Methadone, like all opioids, can cause respiratory depression, but this risk is minimized when methadone is administered once daily in the supervised setting of a methadone clinic. Overdose of methadone can be reversed with naloxone, but small doses should be used and titrated to respiratory function, to prevent acute withdrawal and agitation.

Methadone is the standard of care for pregnant patients with opioid addiction. Although it is category C in pregnancy, risks of methadone are less than the risks to both mother and fetus of continuing to abuse opioids during pregnancy. Neonates born to mothers taking methadone may develop neonatal abstinence syndrome, characterized by temperature instability, gastrointestinal symptoms of diarrhea, vomiting, poor feeding and neurologic symptoms of irritability, increase muscle tone and seizures. All neonates born to mothers receiving methadone should be monitored carefully for these withdrawal symptoms and may require a methadone taper.(5)

Buprenorphine

Buprenorphine, marketed under the trade name Suboxone, is a partial opioid agonist which binds to the mu opioid receptor, and also has weak activity at the delta and kappa opioid receptors.(1,2) As a partial agonist, buprenorphine relieves withdrawal symptoms and craving, but does not induce euphoria. The effects of buprenorphine last for 24-36 hours, making it ideal for daily dosing.

Unlike methadone, which can cause intoxication and respiratory depression at higher doses, buprenorphine has minimal respiratory suppression, and also seems to have a ceiling effect, meaning increasing the dose does not result in a high.(2) As a result, buprenorphine is approved for patients to take daily at home, but can only be prescribed by physicians who have completed a special training. It is administered as a sublingual tablet or an absorbable buccal film. Buprenorphine is combined with naloxone in order to deter patients from abusing it by injection. Naloxone undergoes extensive first-pass metabolism and does not reach the systemic circulation when taken orally or sublingually. However, if patients attempt to get high by injecting the buprenorphine-naloxone, the naloxone component induces rapid withdrawal symptoms.

Buprenorphine brings relief for withdrawal symptoms through its partial agonist affects. However, it will also displace other opioids and can precipitate a painful withdrawal syndrome in a patient actively using opioids. Therefore it is recommended that patients take buprenorphine no sooner than 12 hours after taking a short-acting opioid and 24 hours after taking a long-acting opioid.

Similar to methadone, buprenorphine can result in QT prolongation and caution should be used in patients at risk for QT prolongation.(6) Buprenorphine can result in respiratory depression, but this is usually seen when it is abused by injecting or snorting. For this reason the naloxone component is added to the sublingual formulation to prevent overdose.

Treatment of Acute Pain in Patients on OMT

Patients with opioid addiction develop the same painful conditions as patients without substance abuse disorders, such as fractures, kidney stones and surgical conditions such as appendicitis. Treatment of acute pain in patients with opioid addiction is complicated by factors like heightened pain sensitivity and high opioid tolerance, as well as the provider’s desire to avoid complicating the patient’s recovery by administering narcotics. However, while avoidance of opioids in patients with opioid addiction is ideal, a broken femur or other severe injury will likely require parenteral opioids.

Patients on OMT in particular often require higher doses of oral and parenteral opioids to achieve adequate analgesia, and providers should be aware of this to appropriately manage their painful conditions. However, patients develop greater tolerance to the analgesic effect of opioids than to the respiratory depression effect, so they may have a narrower dose range between analgesic effects and respiratory depression.

Use of Buprenorphine in Acute Withdrawal

Opioid withdrawal symptoms including muscle aches, motor restlessness, anxiety, tremor, abdominal cramping, nausea, vomiting and diarrhea are a common reason patients seek care in the ED.  While not life-threatening, these symptoms are extremely uncomfortable and distressing to patients. Providers typically administer treatments like clonidine, benzodiapezines, NSAIDs and antiemetics, which have modest efficacy at best at relieving symptoms. Patients are often frustrated at the little we have to offer them, and, unable to get into drug treatment programs right away, often go right back to using heroin or illicitly-obtained prescription medications after leaving the emergency department to obtain symptom relief.

However, new data suggests that ED administration of buprenorphine is more effective than clonidine and other standard therapies at relieving symptoms of opioid withdrawal. (7,8) Even more promising, ED administration of buprenorphine results in a higher percentage of patients actually making it to and staying in treatment programs than those treated with standard therapies.(9)

A randomized trial by D’Onofrio et al at an urban ED found that of patients treated with suboxone for their withdrawal symptoms, 78% were still engaged in addiction treatment after 30 days, compared to a dismal 37% who were referred to addiction treatment and 45% who had received a brief intervention and referral. Additionally, patients in the buprenorphine group reported more heroin-free days compared to the other two groups, and were less likely to utilize inpatient addiction treatment services.

Other centers are starting to follow suit and offer buprenorphine for management of acute withdrawal. While this area needs more study, these results are nonetheless very promising, and we may finally have a more effective tool to treat opioid withdrawal symptoms in the ED and get patients on their way to recovery.

Disclosure:

The authors of Rx Pad have no financial or other affiliations with any drug manufacturers or companies.

References

  1. Schuckit MA. Treatment of Opioid-Use Disorders. Longo DL, ed. N Engl J Med. 2016;375(4):357-368. doi:10.1056/NEJMra1604339.
  2. Bart G. Maintenance medication for opiate addiction: the foundation of recovery. J Addict Dis. 2012;31(3):207-225. doi:10.1080/10550887.2012.694598.
  3. Meader N. A comparison of methadone, buprenorphine and alpha2 adrenergic agonists for opioid detoxification: A mixed treatment comparison meta-analysis. Drug Alcohol Depend. 2010;108(1-2):110-114. doi:10.1016/j.drugalcdep.2009.12.008.
  4. Nielsen S, Larance B, Degenhardt L, Gowing L, Kehler C, Lintzeris N. Opioid agonist treatment for pharmaceutical opioid dependent people. Cochrane Database Syst Rev. 2016;(5):CD011117. doi:10.1002/14651858.CD011117.pub2.
  5. Lexicomp: Methadone: Drug information. www.uptodate.com. Accessed February 7, 2018.
  6. Lexicomp: Buprenorphine: Drug information.
  7. Gowing L, Ali R, White JM, Mbewe D. Buprenorphine for managing opioid withdrawal. In: Gowing L, ed. Cochrane Database of Systematic Reviews. Vol 2. Chichester, UK: John Wiley & Sons, Ltd; 2017:CD002025. doi:10.1002/14651858.CD002025.pub5.
  8. Steele A, Cunningham P. A Comparison of Suboxone and Clonidine Treatment Outcomes in Opiate Detoxification. Arch Psychiatr Nurs. 2012;26(4):316-323. doi:10.1016/j.apnu.2011.10.006.
  9. D’Onofrio G, O’Connor PG, Pantalon M V., et al. Emergency Department–Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence. JAMA. 2015;313(16):1636. doi:10.1001/jama.2015.3474.

ABOUT THE AUTHORS

Karen Serrano, MD is an assistant professor in the department of emergency medicine at the University of North Carolina.

Dr. Shenvi is an assistant professor in the department of emergency medicine at the University of North Carolina. She authors RX Pad each month in EPM.

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